Assuring quality, information, and choice in managed care

The aim of the study was to determine whether there is an increase in responsiveness to estrogen stimulation of maternal behavior and lordosis responsiveness during pregnancy. Using separate groups of pregnancy-terminated females, we measured the initial maternal responsiveness of hysterectomized-ovariectomized (HO) females and their responsiveness to estrogen stimulation. Maternal behavior latencies were studied in females HO on the 8th, 10th, 13th, 16th, or 19th day of pregnancy (8HO-19HO) and in nonpregnant HO (NPHO) females. Groups were injected sc with estradiol benzoate (EB) in doses ranging from 0 to 200 microgram(s)/kg and tested for maternal behavior (retrieving, crouching, and licking pups). In addition, we investigated whether there is an increase during pregnancy (following HO) in lordosis responsiveness to estrogen stimulation. Lordosis behavior was studied in pregnant HO females (days 8, 16, and 22) and NPHO females given 0 to 200 microgram(s)/kg EB. There was an increase in maternal responsiveness in oil-treated HO females starting around midpregnancy. From early pregnancy on there was also an increase in maternal responsiveness to 20 microgram(s)/kg EB. In late pregnant females (16HO) there was a further increase with 50 microgram(s)/kg EB. There was no increase in lordosis responsiveness to EB stimulation during pregnancy; pregnant and nonpregnant HO females had the same EB threshold for stimulating lordosis behavior. The results of both studies were related to increases during the latter half of pregnancy in nuclear estrogen receptor concentrations in the MPOA, an area that mediates estrogen stimulation of maternal behavior, and the absence of such increases during pregnancy in the VMH, an area that mediates estrogen stimulation of lordosis behavior.     

Estrogen and the neural mediation of female–male mounting in the rat.

Sexually receptive females mount sexually sluggish males to entice them to copulate, and estrogen and male olfactory cues mediate this female–male mounting (FMM) in the rat. This study examined whether brain regions that concentrate steroid hormones and receive olfactory projections were important for the mediation of FMM. Fos induction was observed within the medial amygdala, medial preoptic area, and ventromedial hypothalamus of ovariectomized, hormone-primed rats that displayed FMM compared with rats that did not. Excitotoxic lesions of those regions eliminated FMM, whereas implants of crystalline estradiol benzoate to the ventromedial hypothalamus, but not the medial preoptic area or medial amygdala, restored FMM. These data indicate that the ventromedial hypothalamus is a critical area of convergence of hormonal, olfactory, and somatosensory inputs for FMM. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine release in the medial preoptic area of female rats in response to hormonal manipulation and sexual activity.

Dopamine (DA) is responsive to hormonal manipulations and has been implicated in the regulation of female rat sexual behavior. In the present studies, extracellular DA levels were assessed in the medial preoptic area (MPOA) of ovariectomized female rats in response to exogenous ovarian hormones and during sexual activity. In female rats primed with a low dose of estradiol benzoate (2 μg), but not with a higher dose (20 μg), a 500-μg progesterone injection increased extracellular DA and facilitated copulatory behavior. Extracellular DA levels in the MPOA were further augmented during sexual interactions with a male rat in a nonpacing copulatory chamber by either perineal or vaginal stimulation. However, in a pacing chamber, DA efflux did not increase, although the metabolites rose significantly during copulation. Together, these findings suggest that extracellular DA in the MPOA responds to the hormonal state of the female rat and may contribute to her expression of sexual behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Physiological and sensorial determinism of maternal behavior in mammals]

In mammals, the development of maternal behaviour is generally controlled by neuroendocrine factors followed by sensory factors. Whereas the dynamics of the steroid balance at parturition are of primary importance in non-human mammals, stimulation of the uterine tract during the expulsion of the foetus is the key-factor in ungulates. This induces a cascade of physiological events and particularly the activation of the oxytocinergic system. The increase in prolactin release appears to be important only in rodents. Activation of the opiate system induces inhibitory effects in rodents and facilitatory effects in ungulates and, in rodents, the medial preoptic area is the central key structure of hormonal action. In women, no correlation exists between hormonal levels and maternal attitudes either during pregnancy or in the post-partum period. Physiological factors enhance receptivity to stimuli coming from the neonate and this allows the female to display maternal behaviour beyond this critical period. Odours facilitate the organisation of both maternal and infantile behaviour and are involved in individual recognition for both. Olfaction may also participate in the regulation of mother-young interactions in humans.     

Identification of estrogen regulated genes in Fe33 rat hepatoma cells by differential display polymerase chain reaction and their hormonal regulation in rat liver and uterus

We applied the differential display RT-PCR (ddRT-PCR) technology to identify estrogen-regulated hepatic genes in the estrogen receptor expressing rat hepatoma cell line Fe33. Three genes of known sequences were detected by the ddRT-PCR approach: IGF binding protein-1 (IGFBP-1), vitamin D-dependent calcium-binding protein (CaBP9k) and major acute phase protein (MAP). Effects of ethinyl estradiol on the mRNA levels of these genes were confirmed by "Northern-blot" analysis. If given in combination with dexamethasone and glucagon, ethinyl estradiol caused 40-, 15- and 11-fold increases in the mRNA steady state level of IGFBP-1, CaBP9k and MAP, respectively, in Fe33 cells 24 h after addition of hormone. Besides ethinyl estradiol, the partial estrogen agonist OH-tamoxifen caused dose dependent effects on expression of MAP and IGFBP-1. Estrogen regulation of the respective genes and the modulatory effects of progesterone (10 mg/animal/day) were studied in ovariectomized rats treated subcutaneously for 14 days with 1 microgram/animal/day estradiol. "Northern-blot" analysis of liver RNA revealed a 6-fold stimulation of IGFBP-1 mRNA levels in estradiol-treated compared to vehicle-treated rats and a weak but detectable increase of MAP mRNA steady state level (1.6-fold) upon estradiol administration. No effect of estradiol treatment could be monitored for CaBP9k in rat liver. Modulatory effects of progesterone on estradiol-stimulated expression in the liver could be monitored for IGFBP-1 only. In an extension of our investigation on the expression of the three genes in rat liver, we determined their expression and hormonal regulation in the uterus of the same animals. In the uterus, estradiol caused an increase in CaBP9k mRNA. In contrast, IGFBP-1 mRNA levels increased dramatically upon progesterone administration, whereas no effect of estradiol treatment could be detected. MAP mRNA levels increased only after coadministration of estradiol and progesterone. In conclusion, the ddRT-PCR proved to be a powerful method to identify estrogen-regulated genes. The study on the hormonal regulation of three genes stimulated by estrogen in Fe33 cells revealed similarities and differences in their regulation in vivo and in vitro.     

Neurons in the lateral subdivision of the habenular complex mediate the hormonal onset of maternal behavior in rats.

Expanding on research showing that radio-frequency-induced lesions of the habenular complex disrupt the hormonal onset of maternal behavior in rats, the authors explored the importance of neurons in the lateral (Lhb) subdivision of the habenular complex for the onset of maternal behavior. On Day 12 of pregnancy, bilateral cytotoxic lesions were produced in the Lhb with kainic acid or, as a control, just dorsal in the medial hippocampus. A 3rd group had radio-frequency-induced Lhb and medial (Mhb) lesions. On Day 16 of pregnancy, Ss were hysterectomized–ovariectomized, given estradiol, and tested 48 hrs later for 10 days. Neuroanatomical tracing with fluoro-gold was then used to directly quantify the extent and location of Lhb neuron loss and to verify that Mhb neurons were intact. Cytotoxic lesions of the entire Lhb prevented the onset of all components of maternal behavior compared with controls. Results show that neurons in the Lhb, not the Mhb, are important for onset of maternal behavior in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Androgen regulation of the insulin-like growth factor-I and the estrogen receptor in rat uterus and liver

For the first time testosterone is shown to be an important regulator of the insulin-like growth factor-I (IGF-I) in the rat uterus under in vivo conditions. In this study the regulation of IGF-I and the estrogen receptor (ER) by gonadal steroids in the uterus and liver of female rats was monitored. The ER level was assayed by hormone binding after treatment with testosterone, 5 alpha-dihydrotestosterone or estradiol and specific mRNA species were analyzed by a solution hybridization/RNase protection assay using 35S-labeled RNA probes. Ovariectomized rats restored uterine weight after treatment with testosterone. Uterine IGF-I mRNA was more than 20-fold higher in testosterone treated rats compared to untreated ovariectomized controls after 48 h treatment. The effects of testosterone on ovariectomized animals was followed in a timecourse study. Testosterone administration increased uterine IGF-I mRNA expression during the first 48 h and the maximally induced level was maintained throughout the duration of the experiment (168 h). Since induction of IGF-I mRNA by estrogen is transient, these data indicate that androgen and estrogen increase IGF-I mRNA by different mechanisms. Regulation of IGF-I mRNA by gonadal steroids was also studied in hypophysectomized animals. The rats were given either testosterone, 5 alpha-dihydrotestosterone or estradiol, and uterine IGF-I mRNA was measured after 1 week of treatment. At this timepoint estrogen treated rats showed levels of IGF-I mRNA not significantly different from those of hypophysectomized controls. In contrast testosterone and 5 alpha-dihydrotestosterone increased the IGF-I mRNA level 30 and 40 times, respectively, relative to hypophysectomized control animals. Since 5 alpha-dihydrotestosterone is not convertable to estrogen, the induction by testosterone was considered to be a true androgenic phenomenon.     

Use of computer interview data to test associations between risk factors and pregnancy outcomes

Estrogens are an important class of steroid hormones, involved in the development of brain, skeletal, and soft tissues. These hormones influence adult behaviors, endocrine state, and a host of other physiological functions. Given the recent cloning of a second estrogen receptor (ER) cDNA (the ER beta), work on alternate spliced forms of ER alpha, and the potential for membrane estrogen receptors, an animal with a null background for ER alpha function is invaluable for distinguishing biological responses of estrogens working via the ER alpha protein and those working via another ER protein. Data generated to date, and reviewed here, indicate that there are profound ramifications of the ER alpha disruption on behavior and neuroendocrine function. First, data on plasma levels of estradiol (E2), testosterone (T), and luteinizing hormone (LH) in wild-type (WT) versus ER alpha- mice confirm that ER alpha is essential in females for normal regulation of the hypothalamic-pituitary gonadal axis. Second, ovariectomized female ER alpha- mice do not display sexual receptivity when treated with a hormonal regime of estrogen and progesterone that induces receptivity in WT littermates. Finally, male sexual behaviors are disrupted in ER alpha- animals. Given decades of data on these topics our findings may seem self-evident. However, these data represent the most direct test currently possible of the specific role of the ER alpha protein on behavior and neuroendocrinology. The ER alpha- mouse can be used to ascertain the specific functions of ER alpha, to suggest functions for the other estrogen receptors, and to study indirect effects of ER alpha on behavior via actions on other receptors, neurotransmitters, and neuropeptides.     

Medial preoptic area and onset of maternal behavior in the rat.

Three experiments examined whether the medial preoptic area (MPOA) is involved in the onset of maternal behavior in the rat. Exp I, with 54 female Charles River CD rats, investigated whether estradiol benzoate (EB) acts on the MPOA to facilitate the onset of maternal behavior in 16-day pregnant, hysterectomized, and ovariectomized Ss. When given EB implants in the MPOA, these Ss had significantly shorter latencies for the onset of maternal behavior than those implanted with cholesterol in the MPOA or with EB in the ventromedial hypothalamus, in mammillary bodies, or under the skin. Exp II, with 62 Ss, showed that estrogen-induced prolactin release was not involved in this facilitation. Exp III, with 35 Ss, showed that MPOA lesions disrupted the onset of maternal behavior induced by pup stimulation in virgin females. (11/2 p ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of estrous cyclicity on the expression of the galanin receptor Gal-R1 in the rat preoptic area: a comparison with the male

Variations in the number of galanin receptor (Gal-R1)-expressing cells and levels of Gal-R1 messenger RNA (mRNA) were determined in the preoptic area in intact female rats throughout the phases of the estrous cycle and compared with those in the male. Female and male Wistar rats were fixed by perfusion with 4% paraformaldehyde. Cryostat sections were hybridized with a 35S-labeled antisense Gal-R1 riboprobe. The number of Gal-R1 mRNA-expressing cells was lower in the rostral preoptic area than in the medial preoptic area. During the estrous cycle, the highest number of Gal-R1 mRNA-expressing cells in the rostral preoptic region was detected at 0800 h on proestrus, whereas in the medial preoptic area, the maximum number was observed at 1800 h on estrus. Gal-R1 mRNA levels in individual cells were low during diestrus and increased at estrus in both areas. In the male, the number of mRNA-expressing cells and the hybridization signal were significantly lower than those in females during estrus. The results demonstrate that Gal-R1 gene expression in the preoptic area varies during the estrous cycle and is low in males. Short term treatment of ovariectomized rats with estradiol plus progesterone caused significantly decreased preoptic Gal-R1 mRNA levels compared with those after treatment with estrogen only. These observations suggest that in the preoptic area, expression of Gal-R1 is influenced by progesterone. The variation in Gal-R1 expression is likely to influence the extent to which galanin can influence the preoptic cells implicated in the control of neighboring GnRH cells.     

Localization of hypothalamic sites for the estrogen-priming of sexual receptivity in female hamsters.

Ovariectomized female hamsters received small unilateral implants of estradiol at a variety of anterior-posterior levels of the medial preoptic area and hypothalamus. The results of an initial experiment using 27-ga. implants showed that females with estradiol implants in the ventromedial hypothalamus (VMN) or nearby anterior hypothalamus consistently showed higher levels of sexual receptivity than did females with implants farther rostral, in the preoptic area, or farther caudal, in the posterior hypothalamus. A second experiment used smaller, 28-ga. implants to compare directly the two areas at which implants were effective in the first experiment. The results confirm the findings of other recent studies of hamsters and rats by identifying the VMN as the most effective hypothalamic site for the estrogen priming of sexual receptivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Patterns of induction of the immediate-early genes c-fos and egr-1 in the female rat brain following differential amounts of mating stimulation

Vaginocervical stimulation received either during mating or by artificial mechanical means has been shown to induce FOS expression in medial amygdala, preoptic area, hypothalamus, and midbrain of female rats. While mating-induced increases in FOS-like immunoreactivity (FOS-IR) have been shown to require intromissive stimulation from males, the pattern of FOS-IR in animals receiving numbers of intromissions across a range relevant to the induction of the prolactin surges of early pregnancy has not been explored. Experiment 1 examined brain FOS-IR following 15 mounts without intromission or 5, 10, or 15 intromissions in ovariectomized females treated with estrogen and progesterone; these treatments are known to be less than or more than sufficient to trigger prolactin surges in cycling females. FOS was expressed in a graded fashion in the medial amygdala with respect to the numbers of intromissions received and in an all-or-nothing manner in preoptic area, bed nucleus of the stria terminalis, and ventromedial nucleus of the hypothalamus. In experiment 2, 15 intromissions induced expression of another immediate-early gene, egr-1, in each of these same areas as well as in a second division of the bed nucleus of the stria terminalis and in the paraventricular nucleus of the hypothalamus. These studies demonstrate that mating is differentially effective in inducing FOS expression in responsive brain areas and point to the medial amygdala as a site in which summation of intromissive stimulation may occur. Furthermore, the induction of EGR-1 may be a more sensitive marker for mating-induced neural activation in these areas than is FOS.     

Gonadal steroids modulate the growth-associated protein GAP-43 (neuromodulin) mRNA in postnatal rat brain

Gonadal steroid hormone action during early postnatal life determines the growth and connectivity of certain neuronal populations in the hypothalamus. The results of recent studies indicate that steroid hormones modulate the growth-associated protein GAP-43 mRNA in the adult rodent hypothalamus. Since GAP-43 is concentrated in axonal growth cones and has been implicated in axonal elongation and synaptogenesis, the present study investigated the effect of various gonadal hormonal conditions on GAP-43 mRNA levels in postnatal rat brain. On postnatal day 1, male rats were castrated or sham-operated and injected with sesame oil. Additional intact female rats were also injected with oil, while a group of female pups were injected with testosterone propionate. On postnatal day 6, brains were frozen and 16-microns cryostat sections processed and hybridized with a 35S-labeled antisense riboprobe complimentary to GAP-43 mRNA. Slide-mounted sections were stringently washed, apposed to X-ray film and then dipped in liquid emulsion. Evaluation of slide and film autoradiograms revealed an extensive presence of GAP-43 mRNA in the medial preoptic nucleus, bed nucleus of the stria terminalis and cerebral cortex, while the intensity of hybridization signal in other brain regions including the striatum was low. Quantitative assessment of GAP-43 mRNA in the medial preoptic area revealed that the level of GAP-43 mRNA was highest in the sham-operated male, attenuated after male castration, low in the intact female and markedly augmented in the testosterone-treated female. The pattern of change in the bed nucleus of the stria terminalis and laminae II and III of the frontal cortex was similar to that observed in the preoptic area. The changes in hybridization signal were positively correlated with changes in serum testosterone levels as determined by RIA. The results of these studies indicate that GAP-43 mRNA levels in the medial preoptic area, bed nucleus of the stria terminalis and cerebral cortex are sexually dimorphic and modulated by changes in gonadal steroid hormone levels. The results further suggest that the differential regulation of GAP-43 mRNA by sex steroids in the male and female postnatal brain may influence the phenotype of forebrain neuronal circuitry and thereby determine the phenotype of adult neuronal function.     

Gadolinium chloride removes pulmonary intravascular macrophages and curtails the degree of ovine lentivirus-induced lymphoid interstitial pneumonia

Estrogens are produced by the aromatization of androgens. These steroids exert their actions after binding to their receptors. Past studies have shown that estrogen receptors (ER) and aromatase enzyme (AROM) reside in many of the same brain regions. Few studies, however, have examined the neural co-localization of these important components involved in estrogen-activated behaviors. In the present study we examined the co-localization of ER and AROM immunoreactive (ir) neurons in musk shrew (Suncus murinus) brains. Data were collected from a representative section from three neural regions, the bed nucleus of the stria terminalis (BNST), medial preoptic area (mPOA), and ventromedial nucleus of the hypothalamus (VMN). Here we report a sex difference in the number of ER-ir neurons from the analyzed section of the mPOA and BNST. Females have more ER-ir neurons in the mPOA and males have more in the BNST. In the sections we examined, males tended to have more aromatase containing neurons than females. Although there were no significant differences in the numbers of double-labeled cells, the VMN contains the greatest percentage of these cells in both males and females; followed by the mPOA and the BNST. In addition, in the mPOA of both sexes, a distinct nucleus of aromatase containing neurons which was devoid of ER immunoreactivity was noted. Area measurements of the AROM-ir nucleus showed that it was significantly larger in males than in females. Taken together, these data suggest that there is not extensive cellular co-localization of estrogen receptors and aromatase enzyme in the musk shrew brain. However, the presence of other genomic forms of ER (membrane and/or ERbeta) in AROM containing neurons has not been ruled out by this study. Thus, we hypothesize that estrogens produced in brain affect behavior by binding to ER in neurons other than those that contain aromatase enzyme.     

Effects of lesions of the amygdala, preoptic area, and hypothalamus on estradiol-induced activity in the female rat.

In the 1st of 2 experiments, lesions of the anterior hypothalamic nucleus and the medial preoptic area sharply attenuated enhancement of wheel running by estradiol benzoate (EB) in ovariectomized albino Holtzman rats. 71 Ss received either 3.0 μg EB or oil in daily sc injections. Lesions of the corticomedial amygdala had no effect on wheel running. The hormonal effects on activity were largely independent of any changes in body weight. Exp I indicated that the anterior hypothalamic and medial preoptic areas are critically involved in the induction of activity by estradiol. However, this experiment provided no support for suggestions that the corticomedial amygdala inhibits those structures that mediate the estrogenic induction of activity. In Exp II, food deprivation was used to stimulate activity. Results suggest that the reduction in the ability of estradiol to induce activity following anterior hypothalamic and medial preoptic lesions does not reflect a general inability to become more active. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sex differences in glutamic acid decarboxylase mRNA in neonatal rat brain: implications for sexual differentiation

Sexual differentiation of rodent brain is dependent upon hormonal exposure during a "critical period" beginning in late gestation and ending in early neonatal life. Steroid hormone action at this time results in anatomical and physiological sexual dimorphisms in adult brain, but the mechanism mediating these changes is essentially unknown. The inhibitory neurotransmitter, GABA, is involved in regulation of sexually dimorphic patterns of behavior and gonadotropin secretion in the adult. Recent evidence suggests that during development GABA is excitatory and provides critical neurotrophic and neuromodulatory influences. We hypothesized that steroid-induced changes in GABAergic neurotransmission during this critical period are important mediators of sexual differentiation in brain. Therefore, we quantified levels of mRNA for GAD, the rate-limiting enzyme in GABA synthesis. On Postnatal Day 1, males had significantly higher levels of GAD mRNA in the dorsomedial nucleus, arcuate nucleus, and CA1 region of hippocampus. On Postnatal Day 15, after the critical period for sexual differentiation has ended, these differences were no longer present. We examined the role of gonadal steroids in regulating GAD by removing testes of males and administering testosterone to females at birth. Exposure to testosterone was correlated with increased GAD mRNA in the dorsomedial nucleus. A sex difference in GAD mRNA was also observed in the medial preoptic area, but the influence of testosterone was inconclusive. We conclude that sex differences in the GABAergic system during development are partially hormonally mediated, and that these differences may contribute to the development of sexually dimorphic characteristics in adult brain.     

Cholinergic influences on estrogen-dependent sexual behavior in female rats.

Examined the ability of cholinergic agents to influence hormone-dependent sexual behavior in Sherman rats. In Exp I, sexual behavior, indicated by the incidence of lordosis, was significantly increased in estrogen-treated Ss following bilateral infusion of a cholinergic receptor agonist, carbachol (.5 μg/cannula) into the medial preoptic area of the brain. Infusion of an artificial cerebrospinal fluid vehicle failed to facilitate lordosis. The incidence of lordosis was normally highest 15 min after carbachol infusion began to wane by 45 min, and had returned to control levels by 90 min. Centrally administered carbachol activated lordosis at lower levels of estrogen priming than did systemically administered progesterone. In Exp II, Ss brought into sexual receptivity by administration of estrogen and progesterone received preoptic infusions of an acetylcholine synthesis inhibitor, hemicholinium-3 (HC-3). Significant reductions in the incidence of lordosis were observed following bilateral infusion of HC-3 (1.25 μg/cannula). This inhibition of lordosis was prevented when carbachol (.5 μg/cannula) was infused along with HC-3. Results confirm the importance of cholinergic influences on sexual behavior in female rats. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sex hormone modulation of neural development in vitro

The sex hormonal milieu during human and primate development is thought to influence adult cognition, perception, and behavior. Similarly in the rat, the neonatal sex hormonal milieu dictates adult behavior, as well as patterns of neural organization within the CNS. Specifically, estrogen and androgen alter neurite outgrowth, neuritic spine development, and synaptogenesis in the limbic system and spinal cord. To examine specific molecular/cellular effects of sex hormones on neurons, in vitro models were developed, using the PC12 cell line. Wild-type cells (PC12-WT) were stably transfected either with an expression vector coding for the human estrogen receptor (ER), androgen receptor (AR), or with a control vector. Resultant clones were isolated, screened for incorporation of vector and expression of ER or AR mRNA and protein, and analyzed for morphologic responses to estrogen and androgen, respectively. PC12-WT, NEO9 (ER-negative, AR-negative), SER8 (ER-positive, AR-negative), and AR8 (ER-negative, AR-positive) cells were exposed to nerve growth factor and graded doses of estradiol or dihydrotestosterone (DHT) for 2 days. In SER8 cells, estradiol led to dose-dependent increases in the frequency of neurite outgrowth, spine development, and interneuritic connectivity. Estradiol increased the frequency of gap junction frequency and length, and functional dye-coupling in SER8 cells. Conversely, in AR8 cells, DHT induced a dose-dependent increase in mean neurite length, branch order, and neuritic field area, while neurite branch segment length and soma area were unaffected. These results suggest that SER8 and AR8 cells in vitro recapitulate various sex hormonal effects on neurons in vivo. Estrogen and androgen appear to induce inherent neural morphologic programs in which androgen increases neurite arborization and the receptive field of individual cells, increasing the likelihood for intercellular communication, while estrogen actually induces this communication, in the form of spines, synapses, and gap junctions. Thus estrogen and androgen act in different but complementary ways to modulate neural development and organization.